Earlier studies have described CB1R-independent actions of AM251 in wild-type and CB1R knockout mice. Here we observed a potent and coordinate induction in the expression of EGFR and its ligands by AM251 in the human PANC-1 pancreatic cancer cell line and HCT116 colon carcinoma cells. This event was associated with enhanced expression of EGFR on the cell surface with concomitant increase in EGF-induced cellular responses in AM251-treated cells. Using genetic, biochemical and pharmacological approaches, we showed that this transcriptional response was NOT related to the modulation of cannabinoid 1 receptor, but, instead, relied on AM251s role as an inverse agonist of estrogen-related receptor &#945;(ERR&#945;). ERR&#945;is an orphan nuclear receptor, whose expression in tumor cells is associated with bad prognosis. Exposure to the synthetic estrogen diethylstilbestrol or the classical inverse agonist XCT790 also induced EGFR and ligands at the transcriptional level to the same extent as AM251, whereas pretreatment with the ERR&#945;selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the proteolytic degradation of ERR&#945;protein without loss of the corresponding mRNA. Knockdown of ERR&#945;by siRNA-based approach led to constitutive induction of EGFR and its ligands and eliminated the biological responses of AM251 and XCT790. Finally, AM251 was found to displace diethylstilbestrol prebound to the ligand-binding domain of ERR&#945;. In summary, this study demonstrates that the CB1R inverse agonist, AM251, exerts off-target effects through binding to and destabilization of the orphan nuclear receptor ERR&#945;in cultured human cancer cell lines. Because of the structural characteristics of AM251 and its clinical analog, rimonabant, future studies will need to be carried out in a panel of normal and cancer cell lines and in vivo models to determine the properties of these compounds as potential endocrine-disrupting chemicals and cancer-inducing agents. Work is underway to determine whether pharmacological interventions provide a viable avenue for interfering with ERR&#945;protein stability in cellular models of various human cancer types and mouse xenograft models. Because of the newly discovered role for ERR&#945;in adaptive energy metabolism, strategies aimed at targeting ERR&#945;may be useful in fighting not only cancer but also metabolic diseases as well. A new investigation on the effect of AM251 on ERR&#945;transcriptional activity will be initiated soon, focusing on histone acetylation and DNA methylation, two major epigenetic molecular mechanisms involved in activation or repression of transcription through changes in chromatin configurations. It is likely that the recruitment of nuclear co-regulatory molecules and other DNA-binding proteins to ERR&#945;at the target gene promoter region is mediated by a mechanism involving epigenetic alterations.